Preparation of desmopressin-containing liposomes for intranasal delivery
Introduction
Desmopressin, a synthetic analog of vasopressin, is used in the treatment of central diabetes insipidus, nocturnal enuresis, mild forms of hemophilia A and von Willebrand disease [1]. Desmopressin is effective after intranasal administration but with poor absorption, and the bioavailability is low in the range from 2.0 to 11.3% [2], [3], [4]. Attempts have been made to enhance desmopressin nasal absorption by using several techniques such as viscous formulation [5], [6], [7], metered-dose nasal spray instead of nose drops [8], lipophilic prodrug formulation [9], and bioadhesive delivery system [7], [10]. Liposome delivery system was found to enhance nasal penetration and absorption of calcitonin or insulin [11], [12]. This was attributed to the increasing nasal retention of peptides [11]. Liposomes also provided protection of the entrapped peptides from enzymatic degradation [13], [14] and disrupted the mucosal membrane to increase absorption of peptides [15]. However, little work has been done on liposomes used as a delivery system for desmopressin in intranasal administration. In the present study, we reported the loading and leakage characteristics of desmopressin-containing liposomes and the effect of liposomes on desmopressin permeation through the rabbit nasal mucosa and antidiuresis in rats after intranasal administration. In terms of charge characteristics of liposomes, we compared their results on the enhancement of antidiuresis.
Section snippets
Materials
Desmopressin was obtained from Penta Inc. (USA). Dioleoylphosphatidylcholine (DOPC) and cholesterol (C) were purchased from Sigma Chemical Co. (USA). Stearylamine (S) and phosphatidylserine (PS) used as positively and negatively charged inducing agents were obtained from Pharmacia P-L Chemicals (Sweden) and Sigma Chemical Co. (USA), respectively. The buffer solutions used for the preparation of liposomes were phosphate-buffered saline (PBS, pH 7.4) and 0.9% sodium chloride solution (pH 4.0,
Results and discussion
The loading efficiency of desmopressin in liposomes against added concentrations of desmopressin during the preparation of liposomes is shown in Fig. 1. The effect of charge characteristics of liposomes on loading efficiency demonstrated that for all liposome preparations the loading efficiency increased with increasing the added concentration of desmopressin until a plateau loading efficiency was attained. Similar results of loading efficiency were obtained for positively charged and neutral
Conclusion
From the results of this study, it seems that liposomes have a good potential as an intranasal delivery system for desmopressin. Positively charged liposomes were able to produce an increase in penetration of desmopressin through the nasal mucosa and a significant enhancement of antidiuresis of desmopressin after intranasal administration. One of the possible mechanisms is the enhanced attachment of positively charged liposomes on the nasal mucosa.
Acknowledgements
This work was supported by VGH89-375.
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